Project 2 started as an ancillary study of lipoprotein metabolism to the NIH sponsored clinical trial of intensive diabetes therapy in type 1 diabetics to prevent microvascular disease called the Diabetes Control and Complication Trial (DCCT). The Epidemiology of Diabetes Intervention and Complications (EDIC) is a ten year non-interventional follow-up of DCCT to evaluate the natural history of macrovascular and nephropathy complications in type 1 diabetes. In DCCT, we found that atherogenic small dense LDL were increased with hyperglycemia, microalbuminuria and were increased in that subset of subjects who gained excess weight as a complication of intensive diabetes therapy during DCCT. Those who gained weight with intensive diabetes therapy were centrally obese, insulin resistant, hypertensive, dyslipidemic and had type 2 diabetic parents. This suggests they had inherited the metabolic-central obesity syndrome in addition to type 1 diabetes. This new proposal will use the phenotypes of 1) excessive weight gain with intensive diabetes therapy and 2) the presence of small dense LDL particles as markers of the central obesity-insulin resistance metabolic syndrome that occurred in this subset of type 1 subjects during intensive diabetes therapy. These markers of the central obesity syndrome will be used to predict the occurrence of cardiovascular events and the development or progression of microalbuminuria during the course of EDIC. Candidate genes for development of the central obesity syndrome and for the interaction of excess weight gain with the development of hypertension will be examined. Intraabdominal fat by CT scan and postheparin plasma hepatic lipase will be measured to further develop the phenotype associated with the excessive weight gain with intensive therapy and with development of nephropathy in the Seattle cohort and three Minnesota cohorts of EDIC. The development of the central obesity syndrome with intensive diabetes therapy in type 1 diabetic patients may predispose them to increased risk of cardiovascular disease and nephropathy. If so, modifications of clinical therapy will need to be made in this subset of individuals.